Nu-aminoindolobenzoquinolizinium compounds



2,933,500 N-ANIINOINDOLOBENZOQUINOLIZINIUBI COMPOUNDS Bernard Rudner, Pittsburgh, Pa., assignor to W. R. Grace & Co., New York, N.Y., a corporation of Connecticut No Drawing. Application November 20, 1958 Serial No. 775,116

12 Claims. (Cl. 260-287) This invention relates to bridgehead nitrogen compounds. In one specific aspect, it relates to derivatives of indolobenzoquinolizine alkaloids which may be called N- aminoindolobenzoquinolizinium compounds. This application is a continuation-in-part of my co-pending application'Serial No. 547,831, filed November 18, 1955, now US. Patent No. 2,891,060.

' A bridgehead nitrogen compound is an organic compound, the molecular structure of which contains at least two mutually fused rings sharing a common nitrogen atom (the bridgehead nitrogen) and at least one other atom. The yohimbane alkaloids contain such a structure. It has been discovered that N-aminoindolobenzoquinolizinium compounds exhibit remarkable hypotensive properties as well as possessing other desirable attributes.

It is, therefore, an object of the present invention to provide a new class of pharmacologically useful compounds.

The compounds of my invention are suitably prepared by the action of chloramine on the appropriate bridgehead nitrogencompound. In the preferred practice of my invention, the reactant amine dissolved in an unreactive solvent is exposed to a stream'of gaseous chloramine. The resultant N -aminoindolobenzoquinolizinium chloride is isolated by conventional laboratory techniques. Compounds containing anions other than chloride are prepared by metathesis, starting with the chloride and a compound containing the anion to be introduced.

In accordance with the present invention, I have made available a new class of compounds having the general formula:

' poses, X must be a pharmaceutically acceptable anion.

United States Patent "ice crystallization, lack of objectionable taste and the like, a

but these considerations are all subsidiary to the characteristics of the cation which are independent of the character of the anion. Hence all variations of X are considered equivalent for the purpose of the present invenand the like.

One method of preparing the novel compounds of my invention is to react chloramine with the tertiary amine corresponding to the desired hydrazinium compound; the

product is isolated and purified by standard laboratory techniques. Since many of the, amines are commercially available as their salts, the hydrochloride being the most common, it has been found convenient to treat aqueous solutions of 'the amine salts with base and extract the free amine with a solvent such as chloroform. After treatment of the extract with a conventional drying agent, the solution is ready for chloramination. While chloramine is most advantageously prepared as a gaseous chloramine-ammonia mixture obtained from a generator constructed according to the teachings of Sisler et al., US. Patent 2,710,248, other methods are equally adaptable for the purpose of the present invention. For instance, chloramine can be made by reacting chlorine with an excess of ammonia in carbon tetrachloride or similar halogenated hydrocarbon solvents under controlled conditions of mixing at low temperatures. Such a process is fully described in US. Patent 2,678,258 to John F. Haller. Another effective procedure is that of Coleman et al. fully described in Inorganic Syntheses, vol. 1, 59 (1939). Alternatively, the chloramine can be formed in the presence of the amine as described in the copending application Serial No. 605,230 filed August 20, 1956, which teaches the reaction of chlorine and a tertiary amine in the presence of excess ammonia. For simplicity, when both the amine and the product are soluble in the same inert solvent, e.g., chloroform, chloramine may be formed in situ by this method right in the solution containing the reactant tertiary amine. In general, the choice of solvent is one of economy and simplicity. When preformed chloramine is used and good adsorption is required for efiicient reaction, it has been found desirable to bubble chloramine through a long column of a solution comprising the tertiary amine dissolved in relatively cheap inert solvent. By inert solvent it is meant a solvent unreactive under the condition of the reaction. Solvents which serve this purpose include hydrocarbons, e.g., heptane, cyclohexane, benzene, xylene and the like; ethers, e.g., diethyl ether, diamyl ether, dioxane and anisole; amides, e.g., dimethylformamide and dimethylacetamide; halohydrocarbons, e.g., chloroform, carbon tetrachloride, trichloroethylene and chlorobenzene; nitroaromatics, e.g., nitrobenzene. For special purposes, water and other hy be used. When the reaction is conducted in anhydrous solution, theprodu'ct often precipitates as the reaction progresses. In aqueous solution, however, it is usually 4 ture and its better known derivatives are illustrated below: V a a necessary to concentrate or to evaporate to dryness in order to isolate the product. Rm

Another method of preparing the novel compounds of my invention is the reaction of hydroXylamine-o-sulfonic acid with tertiary amines which pro duces'the hydrazinlum sulfate corresponding to the tertiary amine used. Pref- 10 erably the appropriate tertiary amine and hydroxyiammeo-sulfonic acid are allowed to react or are heated together in the presence of 'an alcoholic solvent but excess amine or other suitable solvents may be used. Even though Alkaloid R R n" R' (yohimbane) t H H H. H alpha yohimbane COOCHs-.. OH H. H eorynanthine COCO/H3." OH H H reserpine 000C113"- OCH: (GH)C5H2COO OCH; rescinnaminen COOCH3 OOH; (CH3O)C,;H,-,CH=CHCO0 OCH; reserpic ac- COOH OCH; OOH; deserpidine COOOHa- OCH; (CH30)QCH2C OO H the use of a solvent is not required, superior results are obtained'with a solvent because'of the extremely exo- A superficial eiramination of the above; table shows alpha yohimbine and corynanthine to be the same. A

thermic reaction thatquite often results. 'A frequent purification step is the treatment of the reaction mixture with a basic substance such as sodium carbonate to remove acidic constituents from the product hydrazinium sulfate which is essentially neutral and stable to the action. of base. Further purification is effected by standard laboratory techniques. 7 p

It is obvious that not all of theno'vel hydraziniurn compounds of my invention are capable of being prepared directly as shown above. In orderrto provide'the other useful salts of the present invention, it is necessary 'to prepare the compounds 'containinganions other than chloride or sulfate by metathesis. Many of the anions described supra can be obtained by mixing aqueous solutions of the hydraziniurn chloride with appropriate reagents. More often than not, the desired product precipitates directly as the reaction progresses. This is the case where the new salt being formed is less soluble or insoluble in water. Other metathetical approaches are available and the method selected depends onexperimental convenience, costs of reagents and the differences in physical properties between the product and the starting material to be utilized in their separation." Reaction of a hydrazinium halide with a soluble silver salt, such as silver nitrate, results in theprecip'itation of silver halide and the formation of the hydrazinium nitrate. In an analogous manner, treatment of the sulfate with a soluble barium salt results in the precipitation of barium sulfate and conversion to the anion of the barium salt. Quite often the appropriate reactants are heated together in the absence of a solvent and the product isolated by standard laboratory techniques. Another approach independent of the formation of an insoluble solid, is to react the halide with arr-excess of the desired with equivalent amounts of. the appropriate acid maybe system formed by their fusion. In addition, several asymmetric carbon atoms are present and 'thejgeom'etri- *cally permissible stereoisomers can occur. In the case of corynanthine, R and Rf,the carbomethoxy and the by droxyl groups, arebelieved to beds to each othenrings 3 blood pressure without impairing respiration.

utilized; this approach is also used for the preparation of 1 very pure compounds. (subjecting a hydrazinium halide to the action of moist silveroxide, will give the hydrazinium hydroxide.) 7

V The bridgehead nitrogen yohimbanealkaloids suitable as starting materials for the preparation of my novel N-aminoindolobenzoquinolizinium compounds are mostly naturally occurring constituents, of Rauwolfa plants or simple derivatives thereof. The parent yohimbane struc- D and E arethought to becis-fused in the, reserpine family of compounds.

Much brilliant synthetic f'workhas'. been done in the last few years to help ellucidatc the finer points of structure present in Rauwolfa alkaloids but a considerable divergence of view is found regarding the absolute stereochemistry of reserpine,=-the most studied member, and the matter cannot yet be regarded as; settled. It is, therefore, not the purpose of this brief discussionto establish the stereochemistry of each compound-mentioned here "but merely to mention these possibilities so that organic chemists skilled in the art may have a better under standing of the stereoisometric considerations involved.

. Nor is it the purpose of this discussion to limit the scope of my invention to any specific conformation;

The novel compounds of my invention'possess very favorable therapeutic possibilitiesbecause of the exceptionally wide range between the pharmacologically effective dose and those doses which may be harmful or toxic.

My compounds possess the desirable attribute of lowering In addition, these beneficial hypotensive effects have a prolonged duration. These N-aminoindolobenzoquinolizinium compounds display other favorable physiological efiects as will be seen below..

The scope and utility of my invention is further illustrated by the following examples-: I

Example I Chloramine, prepared by means of the jSisler et, al. generator discussed above, 'waspassed intoya solution of 3,0 g. of reserpine in800ml. of chloroform. J The 54:5

and water. After vacuum drying at 607 C., the product was a water and alcohol insoluble-white powder melting above 260 C. somewhat soluble in acetic acid and 3 propylene glycol. Calculated for C H N O CII 60% C, 6.41% H and 6.37% N, found: 59.9% C, 6.58% H and 6.59% N.

Example II tural formula shown below, decomposed ca. 213 C. with some sublimation.

' N N-NH: H V

OCH:

OCH:

OCH:

Hi0 0 o c O CH: 7 Example III A solution containing 100 mg. of N-aminoreserpinium chloride from Example I, ml. of propylene glycol, about 1 g. of water and 0.1 g. of sodium hydroxide was held at 60C. for minutes. The cooled reaction mixture was brought to a pH of 3 by the addition of N hydrochloric acid and the resultant solid collected by filtration and washed well with more dilute acid. On drying, there was found the chloramine adduct of reserpic acid,

melting ca. 221 C. with decomposition; its structural formula is given below. Attempts to prepare the -zwitterion by treating the product with inorganic bases and alkalis failed.

OH J OCH:

Example IV Fifty mg. of the product of Example III and an equal weight of bonzoyl chloride were placed in a stoppered flask containing 10 ml. of pyridine and allowed to stand for two days with intermittent vigorous shaking. The reaction mixture was poured into 60 ml. of a 2% aqueous sodium carbonate solution and allowed to sit overnight at ca. 5 C. before being filtered. After being washed well with water and dried, the product was recrystallized from nitromethane. The chloride-free solid melted 191l93 C. with decomposition and is believed to be the benzoate of N-aminoberizoylreserpic acid having the structure OCH:

I [(CHHQIE AFO] 6. Example V A: solution containing 1.0 g. of yoh imbine hydrochloa ride and 0.4 g. of sodium methoxide in 50 ml. of methyl alcohol was kept atreflux while 0.5 g. of hydroxylamineo-sulfonic acid dissolved in 25 ml. ofv the same solvent was added in small portions. After the addition had been completed, the reaction mixture was refluxed for two hours and the cooled reaction-mixture poured into 50 ml. of 5% acetic acid. N-aminoyohimbinium sulfate was collected by filtratiom washed well with cold water and dried; it structure N s-N112 About mgJof N-aminoyohimbinium sulfate dissolved in 50 ml. of boiling isopropyl alcohol was treated with the equivalent amount of barium chloride suspended in 50 ml. of the same solvent. The reaction mixture was refluxed for two hours and filtered hot. On cooling N- aminoyohirnbinium chloride (melting and decomposing ca. 231 C.) crystallized from the filtrate.

Example VII The general procedure of Example V was repeated with corynanthine hydrochloride in place of its stereoisomer yohimbine hydrochloride. N-aminocorynanthinium sulfate was a white solid melting and decomposing around 258-260 C. It was more stable to light than the starting amine.

Example VIII CHaO N N-NH: H

O CH:

HsCOOC' OOCCH=CH 0013::

on; on;

decomposed about 260 C. and has the 7 Example 1X N aminoreserpinium chloride was suspended .in physiological saline or 0.5% rnethy1 Cellosolve at concentrations of and 50 mg./kg.,'respectively, and administered 'to unstarved male albino miceat dosesjof 100, 3'00"and 1000 mgz/kg. There were no sig'ns observed-rother than slight depression following injection of doses containing 100 to 1000 .mg./kg. No deaths occurred and all animals appeared normal at 24 and 4 8 hours. The acute intraperitoneal 13D 'at"48'hours1appears to be greaterthan glycol. V diluted with physiological saline. A female dog weighing 6.2 kg. received intravenous doses of 0.1, 0.5 and I 2.5 mgJkg. over a period of approximately five and one-half hours. Doses of 0.1 and 0.5 mg./kg. caused marked falls in blood pressure lasting from 5 to 20 minutes with transient slight respiratory stimulation. The 2.5 rug/kg. injection caused a slight rise in blood pres- For purposes of injection, the solution was.

sure followed by a-marked fall; the' lilood pressure did not return to preinjection levels within one hour. *The pressor responses to epinephrine and nor-epinephrine were'markedly antagonized after the 0.1y'mg./kg. dose, but'never completely abolished. The depressor response to acetylcholinewas not significantly afiected during the abolished, after the second-0.1 mgJkg. dose.

To summarize, relatively low doses of the test compound exhibit a markedjdepressant action on the blood pressure with little effecton respiration. The compound apparently possesses both adrenalytic and ganglionic depressant properties and appears toprolong the response to histamine.

:I claim: the general formular :1. Compounds having wherein R is a member selected from ing of hydrogen, carboxy and carboloweralkoxy; R and R' are independentlyselected from the group consisting of hydrogen, hydroxyl and lower alkoxy; R" is a mem 'her selected from the group consisting of hydroxy, benzoyloxy, 'cinnamoyloxy, lower alkoxy benzoyloxy and lower alkoxy cinnamoyloxy; and Xis a pharmaceutically acceptable anion bearing the charge 11.

2. Compounds according to claim 1 wherein R is carboloweralkoxy, R :is lower alkoxy, R," is trimethoxy.

benzoyloxy and R' is'lower alkoxy.

3. Compounds according to claim .1 wherein R is carboxy, R is lower alkoxy, R" is'hydroxy and R is lower alkoxy.

' 4. Compounds according boloweralkoxy, 'R1is hydroxy hydrogen.

5. Compoundsaccording to'clairn '1 wherein R is carboloweralkoxy, R is lower alkoxy, R" is trimethoxycinnamoyloxy and 'R" is lower alkoXy. e I

a 6. Compounds according to claim 1 wherein R is carboxy, Ris lower-alkoxy, R" is benzoyloxy and R is lower alkoxy. r I c 7. N-aminoreserpinium chloride.

8. N-aminoyohirribinium sulfate.

9. N-aminocorynanthinium sulfate.

10. N-aminorescinnaminium chloride. 11. The benzoate of N-aminohenzoylreserpic acid. 12. The chloride of N-aminoreserpic acid.

1 No references cited.

and'R" and .R" are the group consist-- to Jelaiml wherein 'R is cari UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.'2,933,500 April 19; 1960 Bernard Rudner the printed specification error appears in and that the said Letters It is hereby certified that iring coprection of the above numbered'patent requ Patent should read as corrected below.

the structural formula sf as in the patent:

Column 8, lines 3 to 13, hould appear as shown below instead 0 Signedand sealed this 6th day of December 1960.

(SEAL) Attest: KARL AXLINE ROBERT C. WATSON Commissioner of Patents Attest'ing Ofiicer 

1. COMPOUNDS HAVING THE GENERAL FORMULA: 